Ehlers–Danlos Syndrome: A Multisystemic Disorder

Ehlers–Danlos Syndrome—Hypermobility Type: A Much Neglected Multisystemic DisorderPMC fujll-text article; – Rambam Maimonides Med J. 2016 Oct – Yael Gazit, M.D., M.Sc., Giris Jacob, M.D., Ph.D., and Rodney Grahame, C.B.E., M.D., F.R.C.P., F.A.C.P.

Though it includes a recognized EDS expert, be warned that this comes from an obscure medical journal, but…

I found it to be an excellent overview of the many different facets of Ehlers-Danlos Syndrome and of the many sources of pain in EDS.

This would never be published in a mainstream journal because it is far too vague in its findings, using expressions like “may lead to”, “tends to”, “is thought to”, and other imprecise language. But this is a more realistic description of the reality we live, where so many signs and symptoms are vague (except the pain).  

Ehlers–Danlos syndrome (EDS)—hypermobility type (HT) is considered to be the most common subtype of EDS and the least severe one;

EDS-HT is considered to be identical to the joint hypermobility syndrome and manifests with musculoskeletal complaints, joint instability, and soft tissue overuse injury.

Musculoskeletal complaints manifest with joint pain of non-inflammatory origin and/or spinal pain.

Joint instability leads to dislocation or subluxation and involves peripheral joints as well as central joints, including the temporomandibular joints, sacroiliac joints, and hip joints.  

Soft tissue overuse injury may lead to tendonitis and bursitis without joint inflammation in most cases.

Ehlers–Danlos syndrome-HT carries a high potential for disability due to recurrent dislocations and subluxations and chronic pain.

Throughout the years, extra-articular manifestations have been described, including

  • cardiovascular,
  • autonomic nervous system,
  • gastrointestinal,
  • hematologic,
  • ocular,
  • gynecologic,
  • neurologic, and
  • psychiatric manifestations,

emphasizing the multisystemic nature of EDS-HT.

Unfortunately, EDS-HT is under-recognized and inadequately managed, leading to neglect of these patients, which may lead to severe disability that almost certainly could have been avoided.

In this review article we will describe the known manifestations of the extra-articular [non-joint-related] systems.

  • The predominant presenting complaint is pain, which is often widespread and longstanding, with patients reporting pain ranging from 15 days to 45 years. 
  • Chronic pain may start in adolescence (with 75% of hypermobile adolescents reporting symptoms by the age of 15) or even as late as the fifth or sixth decade of life. 
  • Severity sometimes correlates with the degree of joint instability.
  • Fatigue and sleep disturbance, most probably secondary to severe chronic pain, subluxations, and dislocations while changing posture during sleep, are frequently associated. 

Affected individuals are often misdiagnosed with

  • chronic fatigue syndrome,
  • fibromyalgia,
  • depression,
  • hypochondriasis, and/or
  • malingering

prior to recognition of joint laxity and establishment of the correct underlying diagnosis.

Over the last three decades it has become apparent that EDS-HT has a widespread distribution and is not manifested solely in the joints.

Cardiovascular and Autonomic Nervous System Manifestations

  • A mild degree of aortic root dilatation has been found in up to one-third of EDS-HT patients necessitating echocardiographic evaluation and surveillance.
  • Raynaud phenomenon was found in 38% of EDS-HT patients.
  • Patients with EDS-HT may suffer from palpitations, chest pain, dizziness, pre-syncope, and syncope which has been attributed in the past to mitral valve prolapse (MVP).
  • The frequency of MVP among EDS-HT patients was found to be 28%–67% in more recent studies, but its clinical significance is not clear.

Symptoms formerly attributed to MVP are now considered to be related to autonomic dysfunction, which was found to be highly prevalent among EDS-HT patients.

Gastrointestinal Manifestations

  • Gastroesophageal reflux was found in 57% of EDS-HT patients. 
  • Chronic gastrointestinal discomfort was reported in 86% of patients with EDS-HT, attributed to dyspepsia, gastritis, or gastroesophageal reflux.
  • Irritable bowel syndrome was found among 62% of patients.
  • Early satiety and delayed gastric emptying are reported and exacerbated by opioids

Hematologic Manifestations

Easy bruising and bleeding tendency is common in all EDS types, including EDS-HT.

It manifests with

  • prolonged bleeding time, 
  • oral mucosa fragility with mucosal bruises, and
  • menometrorrhagia.

Since coagulation tests are normal, the underlying cause is presumed to be mechanically impaired collagen too weak to afford adequate protection to the capillaries.

This may be conjecture but it is also a valid explanation for many of our problems. Any body structure, like blood vessels and intestines, can be defective when it’s built from our defective collagen.

It is important to note that small and large arterial dissections have not been reported in EDS-HT.

Ocular Manifestations

  • Myopia has been found in up to 50% of EDS-HT patients,and high myopia of more than −6.0 diopters was found in 16% of patients compared with 0% in the control group.
  • Strabismus was found in 7% of EDS-HT pediatric patients (as opposed to only 2%–4% of the general pediatric population), and it is often refractory to surgical correction. 
  • Meyer et al. found size variations and shape abnormalities of collagen fibrils in the extra-ocular muscles that control the movement of the eye

Gynecologic Manifestations

  • Dysmenorrhea and menorrhagia are common and thought to be due to muscle contractions occurring with greater force given the loose connective tissue.
  • Dyspareunia was found among 30%–57% of EDS-HT women, thought to be caused by small tears in the vaginal surface and lack of appropriate vaginal secretions.
  • Pelvic organ prolapse is common, including uterine prolapse which was found in almost 40% of women with EDS-HT

Urologic Manifestations

  • Stress urinary incontinence was found in 40%–70% of women with EDS-HT, often earlier in life, thought to be due to a weakened pelvic floor, which may be worsened to bladder prolapse
  • Fecal incontinence was found in up to almost 15% of EDS-HT patients, as compared to only 2.2% of the general population.
  • Rectal prolapse may also be found among EDS-HT patients.
  • Furthermore, Dordoni et al. reported on two EDS-HT family members who suffered from visceroptosis, including bilateral kidney prolapse, gastric ptosis, liver prolapse, and ovarian and heart prolapse

Obstetric Manifestations

  • While labor and delivery might be rapid (shorter than 4 hours), and premature rupture of membranes is common, pregnancy in women with EDS-HT is generally normal with good maternal and neonatal outcome
  • Pelvic pain and instability necessitate the use of pelvic belt, crutches, and/or bed rest in 26% of women with EDS, the majority being EDS-HT (compared to only 7% among non-affected women). 
  • Varicose veins in the legs and the vulva are more common among pregnant women with EDS-HT
  • Dysautonomia, characterized by lightheadedness, dizziness, fainting, etc., may worsen during pregnancy, and when postural orthostatic tachycardia syndrome (POTS) is present a blood pressure fall was reported

Neurologic Manifestations

A total of 40% of children with EDS-HT and 50% of adults suffer from headaches, characterized as chronic recurrent headaches in the absence of structural, congenital, or acquired central nervous system lesions that correlate with their symptoms.

Many complain of headaches related to the neck or facial pain that might be related to jaw or TMJ problems

Headaches may also be part of dysautonomia, which was found in 78% of EDS-HT patients versus 10% of controls, characterized by dizziness/ lightheadedness and pre-syncopal episodes, which were found in 88% and 83% of patients, respectively

Partial or complete failure of local anesthesia was described during biopsies and dental or obstetric procedures. Hakim and Grahame found local anesthesia resistance in 58% of EDS-HT patients versus 21% of controls.

Proprioceptive acuity has been found to be impaired among EDS-HT adult patients and pediatric patients. 

Postural instability and balance and gait impairment, resulting in increased frequency of falls, were found among EDS-HT patients as compared to matched healthy controls. 

Impaired proprioceptive acuity is thought to influence muscle strength.

I don’t know what they mean by “thought to influence…’, who is doing the thinking, what is it based on.

Therefore, improving muscle strength on the basis of proprioceptive impairment may be more important for reducing activity limitations than just improving muscle strength

Chiari 1 malformation type 1 was found in 4.7% of EDS-HT patients and may be associated with cranio-cervical instability and/or the tethered cord syndrome.

Psychiatric Manifestations

  • Fear of joint pain and/or instability may lead to avoidance behavior (kinesiophobia) and exacerbate dysfunction and disability.
  • Depression and anxiety are more common among EDS-HT patients and are exacerbated by fatigue and pain.

GENERAL REMARKS

The multisystemic nature of EDS-HT results in patients having difficulty coping with the syndrome, as well as medical personnel failing to understand the true nature of the condition.

This may adversely affect the therapeutic relationship, giving rise to

  • skepticism,
  • resentment,
  • distrust, and
  • hostility

on the part of the patient. [and doctor too, perhaps?]

Although EDS-HT is the most common type and the least severe type of EDS, it tends to be underdiagnosed and mistreated, sometimes leading to severe disability that may have been preventable if diagnosed and treated properly.

Receiving a correct diagnosis is necessary in order to access appropriate care pathways, for example, referral for physiotherapy for EDS-HT rather than for an acute single joint problem

Significant neuromuscular and motor development problems have been found among a pediatric population, and delay in diagnosis resulted in poor control of pain and disruption of normal home life, schooling, and physical activities.

Furthermore, they conclude that knowledge of the diagnosis and appropriate interventions are likely to be highly effective in reducing the morbidity and cost to the health and social services.

DIAGNOSIS

Diagnosis relies on the revised Brighton criteria, but it is important to rule out other connective tissue disorders, especially Marfan syndrome and other types of EDS.

Unfortunately, no genetic defect has been found, and for such a prevalent and complex genetic disorder multiple genes might be involved.

MEDICAL MANAGEMENT

Treatment requires multidisciplinary co-operation and consulting with a

  • cardiologist with echocardiogram monitoring every 2–5 years,
  • orthopedic surgeon with a follow-up once a year, oral and
  • maxillofacial surgeon for temporomandibular joint involvement,
  • gastroenterologist when gastrointestinal manifestations are present,
  • ophthalmologist to rule out other connective tissue diseases and when ocular manifestations are present,
  • urologist and urogynecologist when urologic manifestations are suspected,
  • neurologist and neurosurgeon when prolonged headache is present to rule out Chiari 1, and
  • psychiatry when anxiety and/or depression are suspected.

Allergologic consultation may also be needed when there are multiple drug reactions and/or food allergies.

An autonomic nervous system specialist should be consulted when signs and symptoms of POTS or other autonomic nervous system manifestations are present.

Management includes physiotherapy and hydrotherapy aimed at symmetric and generalized muscle strengthening and proprioception acuity improvement, including

  • deep connective tissue manipulations after each session,
  • occupational therapy when wrists and fingers are involved, and
  • cognitive behavioral therapy for proper adjustment to the chronic nature of the condition.

Nutrition has an important role in treating EDS-HT, and nutritional deficiencies should be sought out and treated.

CONCLUSION

Ehlers–Danlos syndrome-HT is a complex hereditary disorder which is multisystemic, probably due to the prevalence of connective tissue in all body systems.

Its gene defect has yet to be found and might be of multigenetic nature, but until then we have to think about the possibility of EDS-HT in every chronic pain patient, and look for joint hypermobility as well as other multisystemic manifestations of this prevalent syndrome.

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